Changes of ticagrelor formulary tiers in the USA: targeting private insurance providers away from government-funded plans.

CONTEXT: Ticagrelor (Brilinta®) is a new oral reversible antiplatelet agent approved by the FDA in July 2011 based on the results of the PLATO (Platelet Inhibition and Patient Outcomes) trial. However, despite very favorable and broad indications, the current clinical utilization of ticagrelor is woefully small. OBJECTIVE: We aimed to compare ticagrelor formulary tiers for major private (n = 8) and government-funded (n = 4) insurance providers for 2012-2013. RESULTS: Over the last year, ticagrelor placement improved, becoming a preferred drug (from Tier 3 in 2012 to Tier 2 in 2013) for Medco, moving from Tier 4 (with a prior approval requirement) to Tier 3 (no prior approval) for the United Health Care Private Plan and achieving Tier 3 status for Apex in 2013. In contrast, ticagrelor placement did not improve for New York Medicaid, retaining Tier 3 status. In addition, many Medicare Part D formularies have significantly worse coverage than most private plans. For example, Humana Medicare Part D has Tier 3 status requiring step therapy and quantity limits, SilverScript (CVS Caremark) Part D is Tier 3 and the American Association of Retired Persons (United Health Care) Medicare Part D is Tier 4 requiring prior approval. CONCLUSIONS: Ticagrelor formulary placement is significantly better for most private providers than for government-funded plans, which may possibly be due to the selective targeting of private insurance providers and the simultaneous avoidance of government-funded plans.

The FDA outlook of events reporting after ticagrelor or clopidogrel in the PLATO Trial: impact of sponsor censoring dates, drug discontinuation, and withdrawal of consent.

BACKGROUND: Censoring by the study sponsor of clinical endpoint events in indication-seeking randomized trials represents a controversial approach since the reported data may be biased in favor of experimental agents due to the obvious conflict of interest. The frequency of drug discontinuation and rates of consent withdrawal may also impact the trial outcomes. PURPOSE: To assess patterns of event reporting dependent on sponsor censoring dates, drug discontinuation and consent withdrawal in the PLATO trial. METHODS: Analysis of the Food and Drug Administration Complete Response Review for ticagrelor. RESULTS: Excluding adjudicated deaths, the distribution for clopidogrel appears more uniform while that for ticagrelor was skewed to the right, suggesting more events were reported after the sponsor censoring end date. PLATO investigators reported 16 unmatched primary endpoint events for ticagrelor immediately following the sponsor censoring date. Twenty-six out of 30 unreported events following early drug discontinuation occurred amongst patients using ticagrelor. More ticagrelor patients withdrew consent (Δ = 47), or were 'not willing' to complete the study (Δ = 87) when compared to clopidogrel. CONCLUSIONS: Site-reported primary endpoints were unequally distributed for clopidogrel and ticagrelor in the PLATO trial. This pattern suggests the importance of questioning the impact of sponsor-mediated censoring on event reporting by investigators in indication-seeking trials. In PLATO, this pattern seems to have favored the experimental drug and may require further assessment.

Stability validation of paraformaldehyde-fixed samples for the assessment of the platelet PECAM-1, P-selectin, and PAR-1 thrombin receptor by flow cytometry.

Sample fixation for storage and/or transportation represents an unsolved challenge for multicenter clinical trials assessing serial changes in platelet activity, or monitoring various antiplatelet regimens. Whole blood flow cytometry represents a major advance in defining platelet function, although special training and expensive equipment is required. We sought to determine how fixation with 2% paraformaldehyde (PFA), and storage of blood samples over 1 week affects the flow cytometry readings for both intact and thrombin-activating four major surface platelet receptors. Whole blood platelet expression of PECAM-1, P-selectin, PAR-1 inactive receptor (SPAN-12), and cleaved (WEDE-15) epitope was assessed immediately after blood draw, after staining with 2% PFA, and at day 1, 3, 5, and 7. The study was performed in 6 volunteers with multiple risk factors for vascular disease, not receiving any antiplatelet agents. Staining with PFA resulted in a slight decrease of fluorescence intensity, especially for PECAM-1, while antigen expression at day 1, 3 and 5 remains consistent, and highly reproducible. At day 7 there was a small but inconsistent trend towards diminished fluorescence intensity. The platelet data were consistent while validated with the isotype-matched irrelevant antibody. These data suggest that there is a 5 day window to perform final flow cytometry readings of whole blood PFA-fixed inactivated platelet samples. In contrast, thrombin activation cause gradual loss of flow cytometry signal, and cannot be recommended for long-term storage. This is critical logistic information for conducting multicenter platelet substudies within the framework of major clinical trials.

Assessment of bleeding events in clinical trials--proposal of a new classification.

Present classifications of bleeding events used in antithrombotic and/or antiplatelet clinical trials are based on the criteria developed by the Thrombolysis In Myocardial Infarction (TIMI) and Global Use of Strategies to Open Coronary Arteries (GUSTO) groups. Introduced more than a decade ago, the 2 classifications used the criteria to better categorize hemorrhagic events after therapy with thrombolytic agents. Recent advances in interventional cardiology, resulting in a domination of percutaneous intracoronary procedures over systemic drug-induced thrombolysis, have substantially changed the clinical characteristics and magnitude of bleeding complications. Moreover, disturbances of the coagulation cascade, as well as platelet inhibition caused directly by antithrombotic and antiplatelet agents, share very specific and well-recognized clinical features not reflected in the existing classifications. Bleeding events after aspirin or clopidogrel, and especially those after more delicate antiplatelet regimens with dipyridamole used in patients after ischemic stroke or transient ischemic attack, are impossible to classify by the present guidelines, other than categorically triaging them altogether to the "minor" category. Uniting entirely different bleeding events as "minor" under-rates their importance and diminishes affiliated risks, creating an illusion that they do not require monitoring and/or changes in antiplatelet or antithrombotic regimens. In reality, such unrecognized and unreported mild complications may transform into more serious bleeds or lead to noncompliance. Unauthorized withdrawal from antiplatelet agents in turn causes rebound platelet activation and higher risk for secondary vascular events. In conclusion, a new classification of bleeding events is introduced (the BleedScore), based on a point accumulation depending on the severity of hemorrhage, which is believed to be more suitable for the assessment of modern, more delicate antithrombotic and antiplatelet therapies, particularly for their realistic assessment in clinical trials.

Effect of tenecteplase versus alteplase on platelets during the first 3 hours of treatment for acute myocardial infarction: the Assessment of the Safety and Efficacy of a New Thrombolytic Agent (ASSENT-2) platelet substudy.

BACKGROUND: Platelets play a pivotal role in the pathogenesis of acute myocardial infarction, as well as in the occurrence of coronary artery reocclusion and bleeding events. Therefore, the success of fibrinolytic therapy may be dependent on its direct effects on platelets. METHODS AND RESULTS: We sought to determine how tenecteplase (TNK) and alteplase (tPA) affect platelets in vitro in human volunteers and ex vivo by use of patient data from the Assessment of the Safety and Efficacy of a New Thrombolytic Agent (ASSENT-2) trial. For the in vitro studies, whole blood from 9 healthy volunteers was incubated with 30 mg TNK and 60 mg tPA. Platelet function was measured by conventional aggregometry, bedside point-of-care devices, and sensitive flow cytometry techniques. For the ex vivo study, 41 patients were selected from the ASSENT-2 trial: 21 had received TNK and 20 had received tPA. Each patient underwent 7 serial blood draws every 30 minutes for 3 hours. Levels of platelet endothelial cell adhesion molecule-1 (PECAM-1), vascular cell adhesion molecule-1 (VCAM-1), P-selectin, beta-thromboglobulin, platelet factor 4, thromboxane, and prostacyclin were measured by enzyme-linked immunosorbent assay. Significant inhibition of conventional and whole blood aggregation and reduced platelet function by point-of-care analyzers were observed for both agents, but mostly in the TNK-treated samples. After incubation with TNK, flow cytometry revealed decreased expression of glycoprotein IIb/IIIa, PECAM-1, vitronectin receptor, CD151, and formation of the platelet-monocyte aggregates. Serial samples from patients in the ASSENT-2 trial showed a significant decrease of soluble platelet-endothelial biomarkers in the TNK group. There was a trend toward decreased platelet function characteristics with tPA; however, these differences were much smaller than those observed with TNK. CONCLUSIONS: Both tPA and TNK were shown to affect platelet function in human volunteers and in patients with AMI early after thrombolysis. The antiplatelet properties of TNK were shown to be more profound than those of tPA. These findings are relevant to ongoing investigations of combination therapy with fibrinolytic and antiplatelet agents in patients with AMI.

Failure of platelet parameters and biomarkers to correlate platelet function to severity and etiology of heart failure in patients enrolled in the EPCOT trial. With special reference to the Hemodyne hemostatic analyzer. Whole Blood Impedance Aggregometry for the Assessment of Platelet Function in Patients with Congestive Heart Failure.

Data from small studies have suggested the presence of platelet abnormalities in patients with congestive heart failure (CHF). We sought to characterize the diagnostic utility of different platelet parameters and platelet-endothelial biomarkers in a random outpatient CHF population investigated in the EPCOT ('Whole Blood Impedance Aggregometry for the Assessment of Platelet Function in Patients with Congestive Heart Failure') Trial. Blood samples were obtained for measurement of platelet contractile force (PCF), whole blood aggregation, shear-induced closure time, expression of glycoprotein (GP) IIb/IIIa, and P-selectin in 100 consecutive patients with CHF. Substantial interindividual variability of platelet characteristics exists in patients with CHF. There were no statistically significant differences when patients were grouped according to incidence of vascular events, emergency revascularization needs, survival, or etiology of heart failure. Aspirin use did not affect instrument readings either. PCF correlates very poorly with whole blood aggregometry (r(2) = 0.023), closure time (r(2) = 0.028), platelet GP IIb/IIIa (r(2) = 0.0028), and P-selectin (r(2) = 0.002) expression. Furthermore, there was no correlation with brain natriuretic peptide concentrations, a marker of severity and prognosis in heart failure reflecting the neurohumoral status. Patients with heart failure enrolled in the EPCOT Trial exhibited a marginal, sometimes oppositely directed change in platelet function, challenging the diagnostic utility of these platelet parameters and biomarkers to serve as useful tools for the identification of platelet abnormalities, for predicting clinical outcomes, or for monitoring antiplatelet strategies in this population. The usefulness of these measurements for assessing platelets in the different clinical settings remains to be explored. Taken together, opposite to our expectations, major clinical characteristics of heart failure did not correlate well with the platelet characteristics investigated in this study.